David's New Book

Thursday, August 16, 2018

Investors Hate Antibiotics - With Good Reason!

Back in the mid-1990s and even beyond the tech crash of the early 2000s, an antibiotic biotech could frequently raise $50-100 million in their first investment round. This was often in the setting of only one or two preclinical assets. Well folks, those days are long gone. 

Private investors are afraid of antibiotics.  In April of this year, I had a chance to speak to several private investors - angels and venture capitalists.  These were folks who strongly believed in the necessity to pursue antibiotic research and development. But they were unanimous in noting that it was becoming more and more difficult to invest in the space.  Among their colleagues there was a clear disdain for the area.  And as I investigated further, I found that this disdain is well founded in data. 

Recent antibiotic launches have been disastrous. Avycaz, tedizolid, dalbavancin, oritavancin all had launches well under $50 million.  Melinta now sells four approved antibiotics and their total sales revenue was under $15 million. Partly as a result of these figures, the market capitalizations of publicly held antibiotic biotech companies remain in the doldrums in spite of recently approved and launched antibiotics in many cases. 

Market Caps –

Achaogen - $252MM
Tetraphase - $163MM
Nabriva - $169MM
Paratek - $319MM
Spero - $191MM
Melinta - $234MM

The dynamic leading to these market cap numbers is an interesting one. When a company goes public, it shares its own data and market projections with investors. The analysts then carry out their own market survey research to one extent or another and come to their own conclusions.  But, in fact, they generally rely heavily on the company’s own projections.  Some CEOs believe that the analysts do not have a good understanding of the antibiotic marketplace and that this leads them to go along with what the company is projecting. But the company has a vested interest in promulgating, shall we say, optimistic forecast numbers. 

An interesting dynamic can be seen with Achaogen. I have no specific information on what sales revenues Achaogen projected.  But analysts generally thought that peak year sales of plazomicin would be around $300 million including both cUTI and CRE bacteremia indications. Their stock price (figure) plummeted from $12 to $5 when they did not achieve approval for the CRE bacteremia indication even though the analysts’ own projections indicated that cUTI would account for 80% of sales revenues. Why? Was this an emotional response to disappointment? Was this a true reflection of what they considered to be an important effect on plazomicin sales? Or was this a return to reality given another impending launch of an antibiotic into a broken marketplace? Or was it all of the above? I don’t know and I haven’t inquired. 

One biotech CEO I have spoken to over the years is praying for one good, strong antibiotic launch to rejuvenate investment in the antibiotics space. I don’t think that even that will be enough at this point. Investors will consider that to be a blip in an otherwise dismal environment. Two good launches might help.  But I honestly don’t see that happening.  

In my view, our only hope for preventing a complete collapse of the antibiotic R&D space is government intervention.  (Wow!! Did I really say that?) Government will have to step in beyond their important and considerable push incentives supporting antibiotic R&D.  They will need to provide substantial pull incentives to fix the broken market. I don’t see any other solution. 

Friday, July 27, 2018

You Too, Achaogen?

I just learned that Achaogen will lay off 80 people in their research and development areas to save money. Achaogen earned its first approval, in the US, of plazomicin, an aminoglycoside antibiotic active against resistant Gram-negative pathogens.  It will probably receive approval in Europe soon. With this success, it is downsizing to focus on commercial success and sacrificing chances of following up with additional products for the antibiotic pipeline from its own R&D efforts. In their press release, the clearly cite the unfavorable commercial environment for new antibiotics as a justification for their decision.  They will continue to purse their efforts to develop a new aminoglycoside and a new, orally available B-lactam-B-lactamase inhibitor. 

Recent experience shows that all segments of the private antibiotic R&D sector are now failing. In rapid succession we have lost antibiotic research efforts in small companies like Achaogen, mid-size companies like the Medicines Company and Allergan and large companies like Novartis. All this, as Achaogen clearly notes, is due to the antibiotic market failure and society’s failure to address the problem. There is no reason to expect that Achaogen will be the last company to drop out under these circumstances. 

This will further erode investor confidence.  Any dream that many harbor of establishing public-private partnerships to further research and development of new antibiotics is crashing against the rocks of the lack of private investor interest in the current climate. 

We need to be asking our leaders (and I use the term with caution) in government what their plan is for staving off disaster. In the US, as we speak, the REVAMP bill that would provide a powerful antidote to the poisonous antibiotic market situation is languishing for lack of support in Congress.  In Europe, there is still a great deal of talk and no action. Are we waiting for the next epidemic of MRSA or VRE comes along?  Are we going to sit on our thumbs until fully resistant Gram-negative bacteria become dominant in our hospitals and nursing homes? 

A recent study from the US National Institutes of Health sounds yet another warning bell. They looked for difficult to treat cases of Gram-negative blood stream infections between 2009 and 2013.  Difficult to treat was defined as resistant to all or most of the commonly used first line antibiotics. They found that only 1% of all such infections fell into that category.  But before you accuse me of crying wolf, you need to read further. Infections caused by E. coli were the most common and the least likely to be resistant.  But infections caused by hospital and long term care pathogens like Klebsiella, Enterobacter, Acinetobacter and Pseudomonas were much more likely to be resistant. Over 18% of Acinetobacter infections were “difficult to treat.” The mortality for difficult to treat infections was 20% higher than that for more susceptible infections. While there are limitations to this retrospective study, it should remind us that without a pipeline of new antibiotics to treat resistant infections, we will continue to lose increasing numbers of patients and to spend more and more of our health care dollar trying to treat these patients rather than having the tools available to treat them effectively from the start. 

There is no excuse to further delay action to deal with the broken antibiotic marketplace and the resulting desultory state of our antibiotic pipeline.

Saturday, July 21, 2018

Everyone Hates the Pharmaceutical Industry!

I think people have good cause to hate the pharmaceutical industry. Their unreasonable prices for specialty drugs (especially in the US), their constant price increases, their political power (in the US), and their seeming disdain for the public health unless it suits their interests all make the industry, shall we say, unpopular.  When I was working at Wyeth, my biggest complaint about our marketing effort was those ads directed at consumers on television and radio. As a physician, these advertisements made my stomach turn.  I heard constant complaints by other physicians whose patients were constantly questioning them about the advertised drugs or even demanding that they be treated with those drugs.  When I inquired of our marketing colleagues, they had lots of ready-made arguments for why these advertisements were better for patients and physicians (to say nothing of Wyeth’s top line). And I have a bridge I can sell you.

Let’s try to be objective here.  Pharmaceutical companies do not exist to protect the public health and they are not charities or non-profit companies.  They exist to benefit their investors and shareholders. And, they argue, the high risk and tremendous cost ($2.6 billion and counting) of bringing a drug to market requires that they take steps to protect their bottom line. 

The industry recognizes that when they do serve the public health, it can improve their bottom line. This is clearly true for drugs that will cure hepatitis C but is manifestly not true for antibiotics.  And this brings me to the point of this short blog.

In order to incentivize the research and development of new and desperately needed antibiotics, we need to provide an attractive market for these drugs.  (See my interview with Pfizer in this regard). To do this, we will provide a prize or reward to companies who get such products approved and on the market.  This money will come from taxpayers or consumers or both.  OK.  Everyone who wants to give more money to the pharmaceutical industry raise your hands! 

And this, ladies and gentlemen, is our dilemma. If we do not fix the broken antibiotic market by providing such a prize through government action, we will run out of effective antibiotics in the next 40-50 years or so (unless we can slow the emergence of resistance further). If we do fix the market, we will be spending taxpayer or consumer money to reward an industry we hate. People in the US Congress are on a knife’s-edge here. 

I believe that if we could put this case to the population in a way that people could understand, we could go a long way to making our representatives more comfortable with this idea. We would have to deal with all the objections that we have all heard before. Why can’t the government discover and develop and commercialize antibiotics instead of the industry since we will have to pay for it anyway? Why shouldn’t we tax the industry to pay for this award? Etc., etc. 

My impression is that very few in Congress are brave enough to take the action we need to save our future. We need to clear the way for them by taking our case directly to their constituents. And we need to do this quickly and be much more effectively than we have been until now. 

Thursday, July 12, 2018

And There Goes Novartis!

News reports and personal communications from Novartis employees document that Novartis is shutting down their antibacterial and antiviral research groups.  Novartis seems to claim that this is because they have not been as productive in antibacterial research as in other areas.  While this may be true – finding new antibiotics is hard – we all know that the bigger reason is that there is no market especially when compared to oncology where Novartis has an outstanding franchise.  According to the Pew Charitable Trust, Novartis has a new monobactam in clinical development phase 2 targeting resistant Gram-negative pathogens. 

The Novartis shutdown has been a long time coming. Novartis has had a schizophrenic approach to antibiotics ever since they first established their research institute in Cambridge, MA.  They had a scientific research group, but their development and commercial groups were never happy with antibiotics. 

I don’t know what will happen to the 140 scientists and others affected by this latest catastrophe – but I wish them all well. We need their talents! 

So, among the large PhRMA players, who still has an antibiotic discovery program? Glaxo-Smith-Kline, Merck and Roche still carry out bench research to discover new antibiotics. Pfizer only has a clinical development program for antibiotics. Its probably only a matter of time for these large companies as well. 

Theoretically, any of the large pharma companies still engaged in antibiotic research or development might be available to license new antibiotics coming from biotech. But the numbers of such companies is shrinking rapidly. And biotech has struggled lately to get large pharma interested in their products.  Examples include Paratek, Achaogen and others. 

Strategically, we – society – are confused.  We keep pouring money into research carried out in small companies or academia to find new antibiotics that no one will develop or commercialize because there is no market. Ultimately, this strategy will fail unless we change course. We must fix the broken market.  Our best chance today is to support the REVAMP act now before the US congress. Call or write your representatives and get them to act before its too late!

Saturday, June 30, 2018

REVAMP - Its Here!!

And its called REVAMP (re-valuing antimicrobial products).  This bill, proposed in the US House of Representatives by Rep John Shimkus, R-Ind. and Rep Tony Cardenas, D-Calif. represents the most important advance in pull incentives since we began discussing them.  AND – its my preferred incentive – a transferable exclusivity voucher.  They express it differently – they call it an exclusivity conveyance but it adds up to the same thing. If a company gets an antibiotic approved and that new product addresses a priority medical need as determined by the CDC priority list, the company would receive up to 12 months additional exclusivity on that product. BUT – that additional exclusivity must be conveyed (transferred) to another product or products. It looks like the exclusivity could also be “conveyed” to other parties – “the holder of a conveyed exclusivity extension period may sell, exchange, convey, or hold for use, such period.” 

This incentive is extremely effective because it could be worth billions of dollars.  And, because it is transferrable between companies, it provides an incentive for investment in start-ups and biotech since large pharma will have a strong incentive to license any product that meets the CDC and HHS criteria.

There are a few conditions for the award –

§  Ensure availability of product for susceptibility device manufacturers
§  Identify, track and publicly report product resistance data and trends
§  Develop written guidelines and procedures for products appropriate use, which includes appropriate promotion practices, education, surveillance, monitoring and stewardship.
§  Develop education and communications strategies for health care professions about appropriate use
§  Submit a stewardship activity assessment to agency every two years 
§  Contribute five percent of the total value of consideration received from the conveyance to the Foundation for the National Institute of Health for early stage antimicrobial research.

The justification for the conveyance of exclusivity to products other than antibiotics is simple.  Many other therapies depend on our ability to treat infections.  Without this, the treatment of cancer, autoimmune disease including arthritis, and simple routine surgeries become much higher risk. The risk of wounds of war also would take us back to civil war days without effective antibiotics. 

The bill is limited to 10 such awards. After the fifth year post-enactment or the fifth award, whichever should come first, the GAO is to evaluate the effectiveness of the program for developing priority antimicrobials, and shall examine the indications, usage, development of resistance and overall societal value of the priority products that have received this award. 

It is impossible to judge how much this blog and your efforts contributed to this decision.  But I notice that the blog has received a large number of views from Washington and Arlington over the last several weeks.  That is very unusual and I suspect that congressional staffers are paying attention. 

Now, we must push our representatives in congress to vote for this bill! Please, once again, contact your representatives and express your strong support for this bill!  


Friday, June 15, 2018

Gottlieb and FDA to the Rescue

This week, Scott Gottieb, our FDA Commissioner, stated that he was examining, along with the Center for Medicare and Medicaid Services (CMS), a possible pull incentive for antibiotics. Specifically, he said, “It is my belief that a licensing model might offer an effective 'pull incentive' that attempts to create a predictable market for antimicrobial drugs that would meet a narrow set of critical, public health criteria.” The idea of licensing instead of paying per dose (as is done currently) would be to license the ability to use the drug for a period of time for a fixed fee. In this case, CMS would pay the license fee. This is one of several models for pull incentives that have been discussed at DRIVE-AB and in other forums. It is not my favorite. But this is remarkable in that someone at this level in this administration is even proposing any pull incentive at all. Of course, because this is CMS, the license would theoretically only cover Medicare and Medicaid recipients. So those of you not covered would still have to get say colistin for your resistant infections (LOL!).

Over 10 years ago, I worked with Dr. Gottlieb on a task force convened by the Manhattan Institute. We worked on using biomarkers and other methods to allow for regulatory approval of needed new medications prior to the time pivotal clinical data might be available. I tried to introduce such a mechanism for antibacterials and antifungals, but the absence of biomarkers for these infections made this a challenge. Our task force may have contributed to FDAs thinking about oncology and perhaps antivirals, however. My work with Dr. Gottlieb convinced me that he shared the frustrations of those working in the antibacterial area that regulatory requirements at the time were too stringent or too uncertain to sustain investment in research. Now that he is FDA’s Commissioner, I’m sure he remembers those discussions and I’m sure he has been following all of our debates around resistance, regulatory pathways and monetary incentives.

On the same front, FDA just released its Draft Guidance for the development of antibacterial and antifungal drugs for limited populations of patients with serious or life threatening conditions or LPAD. While this is a step forward in that it formalizes the existence of such a pathway, the requirements for approval have not changed beyond what has been previously stated by the FDA in their unmet needs guidance and elsewhere.

Nevertheless, Gottlieb’s statement and the LPAD draft guidance are potentially important steps in the fight against antibiotic resistance. To make these steps come to fruition, we need action. We need a clear and above all feasible regulatory pathway forward for studying infections in small populations of patients. We also need significant pull incentives now to fix the broken antibiotic marketplace.

Monday, June 11, 2018

REVIVE: open access to knowledge and resources for the antimicrobial R&D community

GUEST BLOGGERLaura Piddock - Head of Scientific Affairs, Global Research and Development Partnership (GARDP).

webinar June 13!!!

The sulphonamide drugs were first used in patients in the 1930s; this was closely followed by the development of penicillin and the ‘golden age’ of antibiotic discovery. Today, it is a very different situation with few new treatments but increasing numbers of difficult to treat drug-resistant infections. The void in discovery and development of antimicrobial drugs over the last 20 years leaves us facing a future where once treatable infections are becoming life-threatening. 

The discovery void has also created a vacuum in the experience and knowledge of researchers working on antimicrobial research and development (R&D). As an optimist, one of the exciting things I see in my role as Head of Scientific Affairs at GARDP, and Professor of Microbiology at the University of Birmingham, is the promising projects in small to medium sized biotechnology companies and academic research groups who are working to fill the gap in new antimicrobials. One of the things that attracted me to join GARDP is applying my clinical microbiology and research experience to discovery, R&D of new treatments for multi-drug resistant infections. Through GARDP’s Antimicrobial Memory Recovery and Exploratory Programme (AMREP), we aim to recover the knowledge, data, and assets of forgotten, abandoned, or withdrawn antibiotics, and to identify new treatments.

A key element of AMREP is the creation of REVIVE – an online space where researchers can share knowledge and connect with each other. I’ve been lucky enough in my career to be surrounded by, or at least have relatively, easy access to experts I can call upon for advice and support. Ironically, while technology can better connect us today, working in a research field with a steadily decreasing number of experts, can leave researchers new to antimicrobial R&D isolated. 

That’s why we’ve invited seasoned, internationally recognised experts to be part of REVIVE’s ‘match-making’ facility – supporting exchange between early career researchers and those now refocusing their research to address the AMR crisis, whether they be clinical and non-clinical researchers, with world-class experts in antimicrobial R&D. The aim is to improve, accelerate, and streamline antimicrobial drug discovery, R&D by connecting researchers directly with retired and established antimicrobial researchers and developers. 

We’re also connecting people through our webinar series – the first of which is on Wednesday 13 June. I’m delighted David Shlaes is able to join us live to share his extensive knowledge and experience on clinical development for non-developers and focus on traditional development (tiers A and B). This is the first in a series of three webinars with the following sessions discussing development of antibacterial drugs targeting specific pathogens and development of antibacterial drug enhancer combinations. If you’re not able to join us live, all our webinars will be available for you to watch free of charge on REVIVE

In addition to webinars, we’ve co-organized sessions with CARB-X at the recent ECCMID and ASM Microbe conferences. We’re also making these available on REVIVE as not everyone has the time or funding to attend these conferences. Moreover, we’re hoping to recreate part of the ‘attending conference experience’ by organizing follow-up live Q&A webinars for some of these presentations. 

As a researcher in an established academic institution, I am fortunate to have access to most scientific and medical publications. However, this is not the case for the many working in antibiotic R&D – but access to these is critical to keep our knowledge current and challenge our own thinking. With this in mind, the focus of building REVIVE’s resource library is to signpost you to free, open-access resources on antimicrobial drug discovery and development. 

GARDP’s vision through REVIVE is to give the antimicrobial R&D community a space to interact and learn from each other. We want to work with the community and grow REVIVE into a resource that meets your needs. I encourage you to explore REVIVE and send us your feedback.

I look forward to you joining us on 13 June for our webinar.

Wednesday, June 6, 2018

Urgent - Time to Act!

For those of you who have not been following this story closely, the market entry rewards we have been discussing that are intended to fix the broken antibiotics market are not currently part of the Pandemic and All-Hazards Preparedness Reauthorization Act.  This legislation was our best hope of getting something in the budget. I have it on good authority that we should write the following congressional representatives in this regard. 

Rep. Doris Matsui (D-CA) megan.herber@mail.house.gov
Rep. Anna Eshoo (D-CA) rachel.fybel@mail.house.gov
Rep. Brett Guthrie (R-KY) sophie.trainor@mail.house.gov
Rep. Chris Collins (R-NY) charlotte.pineda@mail.house.gov
Rep. Marsha Blackburn (R-TN) meghan.stringer@mail.house.gov

Some talking points for you are included below. 

The antibiotic market is broken. The problem, from the private market view, will not be addressed anytime soon.  

In the meantime, antibiotic resistance is not going away.  The CDC estimates that we lose 23,000 American lives every year and $20 billion in excess costs to the problem of resistance.  Most experts, myself included, believe this is a vast underestimate. The O’Neill commission in the UK estimates that globally we lose 700,000 lives a year today to resistance.  They noted that if current trends continue, we will see over 10 million deaths and one hundred trillion dollars in lost GDP globally by 2050.  Ultimately, we will end up in a world where simple surgery, cancer chemotherapy, wounds of war and routine medical treatment will become dangerous because of the lack of antibiotics available to treat common but resistant infections.

At the same time, investment in antibiotic research and development is at an all time low. Between 2000 and 2010 all but a few large pharmaceutical companies had jettisoned their antibiotic research efforts. In recent years, Astrazeneca, Sanofi, and J&J all followed suit. The Medicines Company and Allergan disinvested within the last year and more companies are likely to follow soon. This is mainly due to lack of market incentive to pursue antibiotic research. Private investors have heard this message and consequently private funding of biotech is in danger as well. 

Even though public funding of antibiotic research has increased, there is no way to bring any resulting products to market without the participation of the private markets. 

To solve this impasse, government must act. The GAIN act did not work because extending exclusivity on a non-profitable product is not an incentive. Some sort of market entry reward is required to fix the broken antibiotic marketplace and re-incentivize private investment in antibiotic research. Most experts estimate the cost of this to the US would be something like $20 billion over ten years.  The consequence of not acting is too horrible to contemplate. 

I am happy to discuss this with you or your staff at any time.  Other experts you can contact include Kevin Outterson, John Rex and David Shlaes. 

Friday, June 1, 2018

Allergan Bails!


I hate being right when it comes to pharmaceutical companies abandoning antibiotic R&D.  But Allergan just announced that they are putting their infectious diseases unit up for sale as I predicted might happen back last November. They seem to be concerned about their falling stock price according to the Reuters report. But finding a buyer at the right price in the current market atmosphere is not going to be easy.  The most logical customer would be Pfizer since they own the rest of world rights to Allergan’s North American antibiotics Teflaro and Avycaz. But rumors suggest that Pfizer is not happy with the antibiotics market either. 

Once again we will have antibiotic developers retiring, unemployed or working in other therapeutic areas. Once again, the world of potential investors in antibiotics will be shivering in their closets. 

Until governments take concrete steps to shore up the failing antibiotics marketplace, we will continue to see companies abandon the area.  We may see biotechs fail simply because they are unable to garner the private investment they need or have no buyers for the products in development. 

With every incident such as this one, we take another step closer to that post-antibiotic era that we all dread so much. 

Sunday, May 27, 2018

Paul Krugman, Nabriva and the Antibiotics Market

What does Paul Krugman, the Nobel Laureate in economics and New York Times columnist have to do with Nabriva and antibiotics?  While I don’t pretend to be nearly as smart as Professor Krugman and I certainly don’t understand economic theory, I do know something about the pharmaceutical marketplace. Krugman recently wrote an editorial where he claimed that any change in drug pricing, such as might be achieved if US Medicare negotiated prices, would simply be made up by a larger sales volume. He argued, therefore, that pharmaceutical companies should not be afraid of this strategy.  

When I worked in the pharmaceutical industry, I remember detailed price-point studies that sometimes would cost a substantial sum to complete.  These studies attempted to determine the best strategy for obtaining the highest return on investment for drugs about to enter the marketplace. They analyzed potential sales volume at various price levels by interviewing physician experts, physicians in daily practice, decision-making pharmacists, insurance company experts and others.  This was performed in various markets but very intensively in the US since it is there that companies have the greatest choice in pricing. These studies would identify an optimal price-volume point.  Of course, since these were just marketing studies, they did not always turn out to be so accurate when the drug would actually hit the market.  Companies would then make adjustments on pricing as needed. But clearly there is no given specific ratio of price to volume for any drug.  This relationship appears to be a complex one with thresholds. 

Therefore, for the first time since I have been reading Krugman’s editorials, I think he is wrong. But I agree that the US should be negotiating drug prices.  I agree with those that argue that the US has been subsidizing pharmaceutical innovation for the rest of the world.  I do not agree with Trump that the rest of the world will change their behavior.  Why would they do that? If we did negotiate lower prices for drugs in the US, there is likely to be a lower investment in pharmaceutical R&D since companies usually reinvest a relatively fixed percentage of profits in R&D. 
Getting back to Nabriva . . . .Nabriva was my first client when I started my consulting business.  I helped them spin out of Sandoz.  They are developing a novel pleuromutilin antibiotic called lefamulin.  It is available in both intravenous and oral formulations. It is active against Gram positive pathogens including MRSA and respiratory pathogens like the pneumococcus, Moraxella and Hemophilus. As I remember it, the oral dose is 3-4 times higher than the intravenous dose because of limited absorption from the GI tract. Before I retired, there was a great deal of discussion on the best clinical trial strategy for the drug.  Since lefamulin would offer another option for the oral treatment serious skin infections with MRSA, I argued that this would be the best way forward and that in this circumstance a high price would be possible – similar to other oral alternatives for treatment of MRSA infections. Others looked at the greater size of the pneumonia marketplace and felt that pneumonia would be the best way forward. They also felt that they could charge a higher price there.  I disagreed since the pneumonia market was mostly generic and cheap.  I felt that in pneumonia a higher price would be much more difficult to justify. I also felt that the safety factor would be a higher hurdle in pneumonia given the other antibiotics sold for that indication. I lost that argument.

Nabriva just released the top line data for their clinical trials in pneumonia. They clearly were as efficacious as their comparator (moxafloxacin), but they had more treatment emergent adverse events during the trials. To me, this is not surprising given the amount of unabsorbed drug that is left in the gut. Thus, in spite of their announcement that their trials were completed and the results were favorable, their stock price dropped. Investors seem to have understood that the adverse event profile plus increasing competition in the pneumonia market will mean that ultimate sales of lefamulin will suffer.  I am still of the opinion that a trial in serious skin infections focusing on oral therapy of MRSA would have been a better option.  There, given other drugs available, some leeway on safety would be expected. Further, it would be easier to justify a high price there compared to pneumonia. 

Will lefamulin be a worthwhile addition to our antibiotic armamentarium?  Absolutely. It is novel and shares almost no cross-resistance with other antibiotics. Its IV and oral dosing is clearly an advantage  - especially in the treatment of serious, antibiotic resistant infections like those caused by MRSA. 

Lefamulin is also an example of the complex volume-price relationship that Krugman failed to consider in his editorial. 

Monday, May 7, 2018

Standard of Care Antibiotics?

One of the major arguments against the use of superiority trials for antibiotics goes as follows. Once a new antibiotic has been shown to be superior to a comparator, the new drug must then become the comparator for all subsequent trials. There are probably two assumptions that underlie this argument. There is an ethical concern about treating patients in a trial where the comparator has been shown not to be the “best available therapy.” The other assumption here, I think, is that the world of physicians will immediately turn to using the superior drug and therefore that the new superior drug will become the “standard of care”.  But, in fact, this last assumption appears to be completely wrong!

As I noted in a previous blog, ceftazidime-avibactam has been shown to be superior to other “standard of care” antibiotics in the treatment of carbapenem-resistant infections.  The standard of care frequently included colistin. Meropenem-vaborbactam is also superior to “best available therapy” (frequently including colistin) in the treatment of carbapenem-resistant infections. In spite of these data, colistin and polymyxin are still used in commonly in the treatment of carbapenem-resistant infections.

The figure shows use of ceftazidime-avibactam from its launch in April of 2015 until November 2017 compared to the use of colistin and polymyxin for carbapenem-resistant infections. Clearly, the superior antibiotic is not being used clinically.  There are probably two major reasons for this behavior. Ceftazidime-avibactam is very expensive – around $8000 for a course of therapy – while colistin/polymyxin is cheap. The other reason is that in spite of being launched in 2015, most automated susceptibility testing devices used in hospitals are still unable to test ceftazidime-avibactam (don’t get me started!). 

Based on these data, there is no reason why a second or third antibiotic cannot be compared to colistin/polymyxin-containing regimens in a superiority-design trial since these regimens continue to be “standard of care” in spite of data suggesting that they shouldn’t be. If physicians see no ethical concern in treating patients with an inferior drug in their everyday practice, should we force them into another behavior in the setting of a clinical trial? 

Personally, I think the ethics of continued use of colistin/polymyxin for most CRE infections is highly questionable. But if these drugs continue to be standard of care – then using them as comparators seems reasonable. 

Wednesday, April 25, 2018

Education for Antibiotic Researchers

The Global Antibiotic Development Partnership (GARDP) has teamed up with CARB-Xto provide training to current and future antibiotic researchers and developers. I have been pushing this since 2004 when I recognized that the continued consolidation within industry and the abandonment of antibiotic research in industry was going to leave us without experienced antibiotic hunters in the near future.  That future has arrived! My experience in reviewing hundreds of grant requests from biotech and academia clearly demonstrates the lack of basic understanding of the fundamentals of drug discovery among today’s generation of would-be antibiotic researchers. A number of us experienced antibiotic researchers are retired, have been fired, or are now working on oncology or autoimmunity or in neurosciences or in diagnostics. Our expertise will be lost if we don’t do something to pass it on to a new generation. I have been trying to find a way forward for this for the last 15 years without success until now. GARDP and CARB-X are stepping up to the plate!

Before I get to the great work by GARDP and CARB-X, I ask – where is the National Institutes of Health here in the US on this? For more on this see one of my blogs from a few years ago. NIH (in spite of their “in kind” participation in CARB-X) is still very much on the sidelines in this educational effort as far as I can tell.

The GARDP-CARB-X effort kicked off last fall at the ASM-ESCMID meeting in Boston with three “bootcamps” for antibiotic researchers (entire talks via the links below). 

Antibiotic Bootcamp: What Makes a Good Hit? Why and How Do You Write a TPP? - https://www.youtube.com/watch?v=FwOtawrQjBs.


Antibiotic Bootcamp: Clinical Microbiology for a Development Program - https://www.youtube.com/watch?v=xfkuFhvOXsg.


Antibiotic Bootcamp: How Does a Molecule Become a Physical Medicine to be Given to a Human - https://www.youtube.com/watch?v=0IUan9LuDBQ.


GARDP and CARB-X just sponsored a symposium at the ECCMID meeting in Madrid, Spain (slides only).


Marco Cavaleri (EMA): EU regulatory tools for expedited antibacterial development programmes


Sumati Nambiar (FDA): US regulatory tools for expedited antibacterial development programmes

William Hope (Liverpool): PK-PD in support of accelerated programmes: how much is enough?

John Rex: Alternatives to (classical) antibiotics: what will it take to convincingly develop a virulence inhibitor or similar indirect agent?

GARDP has started providing a series of webinars. The first three webinars (presented by me) are on Clinical Development and they are specifically targeting scientists and others who are not clinical developers.  The idea is to provide an understanding to discovery researchers of the various development pathways available for new antibiotics and the risks that might be entailed for given types of products. The first webinar, focusing on traditional development pathways (Tiers A and B) has been prerecorded and is available here. A live version will take place on June 13, 2018.  You can preregister to listen and ask questions here.  Two additional webinars in this series will include one on the development of antibiotics targeting specific pathogens and another on enhancers and non-traditional approaches.  The dates for those have yet to be established, but both of them will include a panel of experts to provide information and answer questions. 

GARDP and CARB-X also plan symposia for the ASM Microbe in Atlanta and for the ASM-ESCMID meeting in Lisbon, Portugal later this year. 

I attended the first two bootcamps last year in Boston. I was incredibly impressed with the quality of the presentations, the speakers and the slides.  I am also extremely grateful that all of this is publicly available for anyone who wants to view the program now and in the future. I believe that all of the programs coming from GARDP and CARB-X will provide a similar high level of quality.  What I do not guarantee is that all of the experts will agree with each other on all topics. It’s going to be your problem to work your way through any controversies.  But at the very least, we will all start with a more advanced understanding of the subject.  

Many many thanks to GARDP and CARB-X for taking up this gauntlet and meeting the challenge head on!




Monday, April 16, 2018

Generic Antibiotics on the Edge

Many thanks to Lew Barrett for pointing me to this article

In the struggle to control drug prices, the rapid entry of new drugs into the generic marketplace is a key step.  This was emphasized by the National Academies of Science, Engineering and Medicine in their recent report on drug prices and shortages. 

Lets talk about generic medicines (even though I’m not an expert here). My understanding of the commercial aspect of selling generic drugs is basic. You work hard to identify the cheapest route to manufacture that you can. You set a price to maximize your margin.  You understand that as more manufacturers enter the field your sales volume will drop. So you keep working on that chemical synthesis and on your suppliers and supply chain to maximize efficiency.  This allows you drop your price while still maintaining enough margin to compensate for your decreased volume of sales. Is there a limit to this strategy? Apparently. 

A 10 day supply of trimethoprim-sulfamethoxazole (Bactrim, Septra, generic) costs from $.4.00 to $15.00 depending on your pharmacy.  That is $0.20-.75 per pill. A “Z-pack” of generic azithromycin runs $7.00-25.00 for the six tablets. According to the article by Cynthia Koons of Bloomberg Business, 90% of drug prescriptions in the US are filled with generic medicines. Generic drug prices are falling about 11% a year according to Koons. This is partly fueled by the domination of only a few giant drug purchasers in the US.  These large purchasers continue to pressure generic manufacturers on price. The generic manufacturers are, in turn, forced to compensate by selling drugs where margins are higher.  Antibiotics are apparently not among this group. Brendan O’Grady noted that Teva, where he is Executive VP for their North American business, still makes antibiotics – but Teva wonders why.

At the same time, drug pricing has become a hot-button political issue here in the US. The price gouging by Mylan for their Epi-Pen and, of course, that of the now infamous Mr. Shkreli and his $750 per pill price for the antiparasitic pyrimethamine used to treat opportunistic infections in immunocompromised patients, have inflamed public opinion.  Congress is not in the mood to support higher drug prices. Yet some reasonable strategy for drug pricing is required and this strategy might involve assuring some minimum value-based price for important drugs like, say, penicillin. This recommendation was, in fact, one of many from the National Academies.

Unfortunately, though, if Congress does not take this seemingly counter-intuitive step, we will continue to suffer more and more drug shortages. As the National Academies report notes, “drugs that are not affordable are of little value while drugs that do not exist are of no value.”  

It’s the triple whammy! Congress needs to provide financial support for new research and development of new antibiotics, money to fix the broken antibiotic marketplace, and support for pricing of generic antibiotics. Wow!  And Congress still seems unable to tie its own shoelaces . . . .

Thursday, April 5, 2018

Reflecting on Antibiotic R&D and Pull Incentives

Today I would like to reflect with you on what I have heard from investors, Pfizer, J&J and various biotech company executives concerning antibiotic R&D, the antibiotic marketplace and the potential role of pull incentives.  

One major problem is that pull incentives remain hypothetical.  Even in the hypothetical, the value of any potential incentive remains completely unknown.  Because of this, investors are essentially ignoring pull incentives, but are very focused on non-dilutive funding via push incentives. I am hearing that we are now experiencing another down cycle in antibiotic biotech investing in spite of the increasing opportunities for push incentives (CARB-X, Novo, Wellcome, BARDA). A recent survey of biotech investments shows that among the top ten life sciences investors, only Entasis, Spero and Nabriva among antibiotic R&D biotechs were recipients of their investments.  Most money pours into oncology and immunology biotech. A recent conversation with a top antibiotic investor confirms this current down cycle for me.

Biotech executives tell me that pull incentives play no role in their plans nor are they discussed in any serious way by their investors. Non-dilutive funding, however, plays an important role in their considerations. All agree that without more successful antibiotic launches, the investment future for antibiotic R&D will be bleak. Where they disagree is on what type of product will be required for a successful launch. Some say that the only way to go is with a relatively broad-spectrum antibiotic that can be used in empiric therapy.  Others say that a pathogen-specific antibiotic can garner a high price and also be successful. My personal opinion is that the high price strategy has, at least so far, been a dismal failure. (See my blog on price perversion). 
From large PhRMA, I have two opinions.  Actually, there is only one opinion and one obfuscation. Pfizer was quite clear. They look at antibiotic investing like any other potential portfolio opportunity. They are clear that they view the scientific risk of antibiotic discovery as simply to high to justify investment even with available push incentives at least given the current state of affairs. They are also clear that a substantial pull incentive will be required for them to invest in late stage antibiotic assets if the assets are to survive their portfolio review process. 

J&Jwas anything but clear. They start with their scientific expertise.  Although I know a number of antibiotic R&D experts who remain within J&J, I am not sure that they have the internal expertise to evaluate antibiotic opportunities.  They seem more interested in “global” needs such as treatment for resistant TB and gonorrhea. And they have demonstrated their commitment to TB with actual products from which they will gain no profits (their priority review voucher notwithstanding). Of course, this is nothing but laudable.  They would not really address any specific issues around what a pull incentive would need to look like for an antibiotic program targeting say resistant Gram negative pathogens to be adopted at J&J.  This makes me believe that such a program has little (but perhaps not zero) chance at J&J regardless of any pull incentive.

The events of the last several years leave me believing that we are standing on a cliff looking into the abyss. Astrazeneca’s spin-off of its antibiotic research assets into Entasis and its sale of marketed antibiotic assets to Pfizer was a beginning. This year we have seen the loss of another large PhRMA company from antibiotic R&D – Sanofi.  This is all the more ironic since they had reentered antibiotic R&D after having jettisoned their assets to form Novexel – the company that ultimately gave birth to avibactam. Once again, Sanofi spun out their assets (while retaining some rights) – this time to Evotec.  Nevertheless, every loss of a large PhRMA hurts because we lose their deep pocket support for the area.  The loss of the Medicines Company, a small pharma company, was especially discouraging since this occurred just after they had won approval for their meropenem-vaborbactam combination antibiotic. I firmly believe that the availability of substantial pull incentives would have altered at least some of these corporate decisions.

I have reason to believe that more losses are coming. Only the successful launch of a new antibiotic or the implementation of substantial pull incentives can keep us from the abyss.